Childhood maltreatment experiences are associated with increased risk of drug and alcohol addiction (e.g. Kendler et al. 2000;Ullman et al. 2005). Models of addiction support the existence of a general addiction risk factor (i.e. not drug- or alcohol-specific) that is substantially accounted for by genetic influences (e.g. Kendler et al. 2003). Using data from identical and fraternal twins, the effect of exposure to childhood maltreatment on the relative influence of genetics on adult lifetime drug and alcohol addiction will be estimated, examining addiction in terms of specific substances (alcohol, cannabis, cocaine), as well as a single poly-drug measure. Previous studies have identified candidate genes that influence drug and alcohol addiction (e.g. GABRA2, Edenberg et al. 2004;CHRM2, Wang et al. 2004). Studies examining how the environment alters genetic influences on mental disorders provide evidence that stressful life experiences alter certain gene effects on disorders such as antisocial behavior and depression (e.g. Caspi et al. 2002;Caspi et al. 2003). The effect of childhood maltreatment on GABRA2 and CHRM2 gene influences on addiction will be examined. A genome- wide association study (GWAS, which utilizes genetic information across all DNA, rather than a specific targeted gene) will then be conducted to identify single nucleotide polymorphisms (SNPs, individual pieces of DNA that differ between people) that either: 1) affect addiction risk regardless of exposure to maltreatment, or 2) influence addiction differently depending on whether the individual experienced childhood maltreatment. A method of biological prioritization will be implemented to preferentially interpret the influence of SNPs that form clusters based on biological function, which may better inform mechanisms of substance dependence. This research will advance the current understanding of addiction by taking a multifaceted approach. First, it will improve our accuracy of measuring addiction risk by taking into account a range of substances. Next, it will examine the overall impact of maltreatment on the relative influence of genes on addiction. Finally, it will examine actual genetic influence on addiction by combining both a specific, directed approach (candidate gene analysis) with a genome-wide search for newly-implicated genes, and investigating how environmental conditions (in this case, maltreatment exposure) affect how genes influence addiction. By combining methods of increasing measurement accuracy with multiple approaches to genetic analysis, and taking into account an environment of established importance in addiction, this research will provide novel insight into the development and mechanisms of addiction, which is a necessary precursor to the development of optimally efficient and effective prevention and intervention public health strategies. PUBLIC HEALTH RELEVANCE: Drug and alcohol addiction take a huge toll on society and the individual, and more than one in four Americans will struggle with drug or alcohol addiction at some point in their lives (e.g. Kessler et al 1994). Childhood maltreatment is consistently associated with a greater risk of drug and alcohol addiction (e.g. Kendler et al. 2000;Ullman et al. 2005) and though the causes are unclear (Wiechelt 2007), the relationship between maltreatment and addiction is stronger for females than for males, and may result from self- medicating (Gutierres &Van Puymbroeck, 2006). By combining increased addiction measurement accuracy with multiple approaches to genetic analysis, and taking into account an environment of established importance in addiction (i.e. childhood maltreatment), this research will provide novel insight into the development and mechanisms of addiction, which is a necessary precursor to the development of optimally efficient and effective prevention and intervention public health strategies.